Tetra Discovery Partners is submitting a Phase II SBIR application to develop a phosphodiesterase-4D (PDE4D) PET tracer for imaging the distribution of the enzyme in human brain. Tetra is a clinical stage biotechnology company that is developing BPN14770, a PDE4D negative allosteric modulator (PDE4D-NAM), as a treatment for cognitive impairment in Alzheimer?s disease, other dementias and psychiatric disorders including schizophrenia and major depressive disorder (MDD). Human studies with the PDE4D PET tracer may benefit patients by improving understanding of how changes in cAMP signaling and altered regulation of PDE4 subtypes contribute to the pathophysiology of disease. The PET tracer will be useful for determining the dose of BPN14770 to be used in pivotal human clinical trials by assessing PDE4D target occupancy in brain. The target occupancy study adds value to the BPN14770 neurotherapeutic and is a critical gate keeper for partnering the drug program with a larger pharmaceutical company. Tetra has completed a successful Phase I SBIR in which a lead PET tracer has been developed that shows specific, displaceable binding to PDE4D in rhesus monkey brain. PET imaging was performed in monkeys as only primate PDE4D contains a key phenylalanine residue on the UCR2 regulatory domain required for PDE4D subtype selectivity. The PET imaging study revealed an intriguing pattern of specific PDE4D binding in regions of the brain known to be important for cognition, namely prefrontal cortex, temporal cortex and hippocampus. However, accumulation of radiolabeled metabolites precludes further advancement of the compound. The Phase II SBIR proposes a straightforward chemical optimization strategy to address this issue. The goal of the Phase II SBIR is to optimize a PDE4D PET ligand for advancement into human clinical trials.